Each year, an estimated 280 million people are affected by and 1-2 million deaths occur as a consequence of the symptoms of malaria following exposure to a Plasmodium spp. Control efforts have been limited by the lack of progress in vaccine development, development and spread of Plasmodium strains resistant to antimalarial drugs, development of pesticide resistance in mosquito vectors, and the general decline in organized mosquito vector control programs. The long-term objectives of the proposed research are to identify, isolate, and characterize genes associated with the susceptibility and/or refractoriness of mosquito species, and to utilize this information to develop a malaria control strategy based on the genetic disruption of mosquito vector competence. The objectives of this project are based on the general hypothesis that genes associated with Plasmodium refractoriness can be identified and isolated via determination of their genetic linkage associations with restriction fragment length polymorphism (RFLP) markers. The research described primarily examines the mosquito Aedes aegypti and its genetic relationship with the malarial parasite Plasmodium gallinaceum as a model system for elucidating genetic control mechanisms, because of the wealth of knowledge available concerning the genetics of this vector and the close phylogenetic relationship of this parasite and the major human malarial parasite P. falciparum. Additionally, some of the proposed research involves a primary vector for P. falciparum, Anopheles gambiae. The specific aims of this project are: (1) to isolate genes that influence Plasmodium susceptibility in Ae. aegypti using map-based cloning techniques, (2) determine the potential of candidate genes isolated in specific aim 1 to positively or negatively influence the development of P. gallinaceum in Ae. aegypti using virus expression systems in cooperation with Colorado State University, (3) examine the potential effects of parasite-imposed selection on RFLP allele frequencies over time in laboratory populations, and (4) construct a preliminary RFLP linkage map for An. gambiae using markers developed for Ae. aegypti in cooperation with The Johns Hopkins University.